a) There is some debate as to the effect of coingestion of medications that decrease gastrointestinal motility (anticholinergic and opioids) may have on the reliability of a 4-hour acetaminophen concentration for risk stratification. Some experts recommend obtaining a second acetaminophen concentration 8 hours postingestion and starting acetylcysteine if either concentration is above the possible toxicity line. Similar recommendations have been made regarding sustained-release acetaminophen products.

a) ST depression and elevation and T wave inversion and flattening have been reported with acetaminophen poisoning (Will & Tomkins, 1971; Weston et al, 1976; Maclean et al, 1968; Lip & Vale, 1996). CPK elevation and pericarditis have also been reported (Weston et al, 1976; Rumack & Matthew, 1975; Maclean et al, 1968; Lip & Vale, 1996).
b) Junctional rhythm and anterolateral T wave inversion developed in a 29-year-old man with moderate hepatotoxicity after acetaminophen ingestion (Armour & Slater, 1993).

a) Autopsy findings have included the following:

a) Hypotension and shock with hypothermia, in the absence of hepatic dysfunction, have been reported following acute acetaminophen overdose. The mechanism of acetaminophen-induced hypotension is unclear (Yang et al, 2001).

a) In a retrospective study of 24 patients with hepatic failure following acetaminophen poisoning, 8 developed severe lung injury and 1 mild to moderate injury. Pulmonary artery occlusion pressures were normal, systemic vascular resistance was low, pulmonary artery pressure was mildly increased and pulmonary vascular resistance was low. Patients with pulmonary injury were more likely to have increased intracranial pressure and circulatory failure, had more severe hepatic coma scores on admission and had a higher mortality rate (8 of 9 (89%) vs 2 of 15 (13%)) than did patients without lung injury (Baudouin et al, 1995).
b) CASE REPORT: Inadvertent intravenous administration of one gram of acetaminophen suspension to a 16-year-old girl resulted in acute respiratory distress syndrome (ARDS). Presumably, microemboli in the pulmonary vasculature resulted in ARDS. The girl improved following heparin therapy and steroids and standard respiratory and cardiovascular support (Burmester et al, 2001).

a) Coma and metabolic acidosis have been reported within 3 to 4 hours of acetaminophen overdose in the absence of hepatotoxicity or co-ingestants in patients with extremely large ingestions (75 to 100 grams in adults and 10 grams in a 1-year-old and in an 18-month-old) and/or extremely high acetaminophen levels (over 800 mcg/mL at 4 to 12 hours postingestion) (Flanagan & Mant, 1986; Zezulka & Wright, 1982; Leih-Lai et al, 1984; Kadri et al, 1988; Roth et al, 1999; Koulouris et al, 1999; Yang et al, 2001; Steelman et al, 2004; Mendoza et al, 2006).

a) CASE REPORT: An 11-year-old child experienced vomiting and a postural headache 2 hours after inadvertent epidural administration of 30 mL of acetaminophen over a 10-minute period instead of intravenous administration. The patient recovered 36 hours later, without sequelae, following supportive care. It is believed that the vomiting and headache may have been a result of a mechanical instead of a toxic complication. The amount of paracetamol in the epidural space filled the space quickly and increased pressure in the space internally, resulting in increased tension at the meningeal structures which had a weak point at the place of puncture of the dural tap. It is speculated that the weak point was reopened and widened, allowing cerebrospinal fluid leakage, thereby causing the headache and vomiting (Courreges, 2005).

a) Cerebral edema is typically present in patients who die from acetaminophen-induced hepatic failure. However, according to a retrospective analysis involving 21 patients who developed fulminant hepatic failure following fatal paracetamol (acetaminophen) overdose, cerebral edema was absent in 8 patients. Further analysis of those patients showed that they were significantly older, they had a lower arterial pH on admission, there was a shorter interval between overdose and death, and there was a shorter interval between hospital admission and death compared with the patients who had cerebral edema. The cause of death in those patients without cerebral edema was primarily cardiovascular collapse with rapidly progressive refractory hypotension and/or cardiac arrest (McCormick et al, 2003).

a) Gastrointestinal irritability may develop immediately following ingestion or up to 12 to 24 hours later: anorexia, nausea, and vomiting may be accompanied by diaphoresis.
b) CASE REPORT: An 11-year-old child experienced vomiting and a postural headache 2 hours after inadvertent epidural administration of 30 mL of paracetamol (acetaminophen) over a 10-minute period instead of intravenous administration. The patient recovered 36 hours later, without sequelae, following supportive care (Courreges, 2005). It is believed that the vomiting and headache may have been a result of a mechanical instead of a toxic complication. The amount of paracetamol in the epidural space filled the space quickly and increased pressure in the space internally, resulting in increased tension at the meningeal structures which had a weak point at the place of puncture of the dural tap. It is speculated that the weak point was reopened and widened, allowing cerebrospinal fluid leakage, thereby causing the headache and vomiting.

a) Fatal hemorrhage from esophageal varices developed 13 days after acetaminophen overdose in a patient with severe hepatotoxicity (Thornton & Losowsky, 1989).

a) Hyperamylasemia and hemorrhagic pancreatitis have been reported, generally developing 2 to 3 days after acute acetaminophen overdose (Caldarola et al, 1986; Gilmore & Touvras, 1977; Coward, 1977; Mofenson et al, 1991; Yang et al, 2001). Acute pancreatitis with hyperamylasemia has been reported following acetaminophen overdose in a hemodialysis patient (Farrell & Schmitz, 1997).
b) Hyperamylasemia was reported in 18% of 290 acetaminophen overdoses. Peak amylase levels developed 2 days after ingestion. Clinical signs of pancreatitis were often obscured by gastrointestinal symptoms and hepatitis (Hord et al, 1992).
c) A retrospective study, conducted to determine the incidence and prognostic implications of hyperamylasemia in acetaminophen poisoning, revealed that the incidence and severity of hyperamylasemia (serum amylase level greater than 100 units/L) appeared to increase with the severity of hepatotoxicity induced by paracetamol poisoning, with hyperamylasemia occurring in 57 of 76 survivors (75%) from fulminant hepatic failure and in 61 of 72 non-survivors (85%) compared with hyperamylasemia occurring in 128 of 666 patients (19%) without fulminant hepatic failure. Fifty-five of 168 patients (33%) with a serum amylase level of greater than 150 units/L either died or underwent liver transplants compared with 17 of 646 patients (2.6%) with a serum amylase level of 150 units/L or less. Clinical acute pancreatitis was a less frequent occurrence, with only 14% of patients with paracetamol-associated hyperamylasemia having clinical evidence of pancreatitis (Schmidt & Dalhoff, 2004).

a) Hepatocellular injury is reflected by a marked rise in transaminase levels. Hepatotoxicity can be severe. Laboratory abnormalities may begin to develop 24 hours after overdose and peak 3 to 4 days postingestion. Clinical signs and symptoms of hepatotoxicity are usually delayed for 3 to 4 days after overdose. Dose dependent hepatic necrosis commonly presents within 2 to 4 days after a toxic dose.
b) Vomiting, right-sided abdominal pain, and symptoms of impending hepatic coma and hypoglycemia may develop 3 to 4 days after ingestion.
c) Elevated blood levels of liver enzymes (SGOT/ALT, SGPT/AST) may begin to develop within 24 hours after overdose and peak 2 to 3 days post ingestion. Increased total bilirubin and prolonged PT may also occur in some patients within 24 hours of acetaminophen ingestion (Singer et al, 1995).
d) CASE REPORT: A 22-year-old man intentionally ingested 15 to 25 hydrocodone/acetaminophen tablets (5 mg/500 mg) and presented to the emergency department 16 hours postingestion after experiencing persistent nausea and vomiting. His acetaminophen concentration, at the time of presentation, was less than 10 mcg/mL and his liver enzyme concentrations were normal (AST 31 units/L (reference range, 0 to 40 units/L), ALT 34 units/L (reference range, 0 to 40 units/L)). At this time, he was transferred to an inpatient psychiatric unit where he continued to experience nausea and vomiting as well as diffuse abdominal pain. Approximately 29 and 36 hours postingestion, repeat laboratory analyses revealed an acetaminophen concentration of less than 10 mcg/mL and an AST of 45 and 150, respectively, and an ALT of 61 and 204, respectively. Due to increasing transaminase concentrations and persistent nausea and abdominal pain over the next 2 days, IV NAC was administered for 16 hours. The patient's liver enzyme concentrations decreased with complete symptom resolution approximately 77 hours postingestion (Bebarta et al, 2014).
e) CASE REPORT: A 28-year-old woman, 36 weeks pregnant, presented with vomiting, decreased fetal movements, and a small hemorrhage of 250 mL. Her medications included enoxaparin, 1 mg/kg twice daily, to treat bilateral pulmonary thromboemboli diagnosed at 28 weeks gestation, but was discontinued two days prior to presentation. Following approximately 14 hours of observation, the patient developed irregular uterine contractions and decelerations of the fetal heart rate, and an emergent cesarean section was performed. Postoperatively, the patient developed persistent tachycardia, somnolence, and nausea. Laboratory data revealed an ALT concentration of 650 International units/L (normal range, 5 to 38 international units/L), lactate dehydrogenase of 3830 International units/L (normal range, 240 to 490 international units/L), a bilirubin of 65 mcmol/L (normal range, 2 to 17 mcmol/L), and platelets of 90 x 10(9)/L. She also developed right upper quadrant abdominal tenderness. She was diagnosed with HELLP syndrome and was treated with fluid restriction and IV magnesium sulfate. Over the next several hours, her liver enzymes continued to increase, her INR was 5.8, and a serum paracetamol concentration, obtained at hospital admission, was 111 mg/L. NAC infusion was initiated, IV fluids were given, magnesium sulfate was discontinued, and the patient gradually recovered. Interview of the patient revealed that she had ingested at least 25 g paracetamol over the course of 24 to 36 hours prior to admission due to back pain and stress. Of note, the neonate also received NAC for prenatal paracetamol exposure. Laboratory tests showed an elevated bilirubin and mildly elevated transaminases but no coagulopathy (Mills et al, 2014).
f) Most cases of acetaminophen-induced hepatic toxicity are the result of oral ingestion of acetaminophen; however, there have been cases of hepatic toxicity reported after intravenous administration of paracetamol and of propacetamol, the diethylaminoacetate ester of paracetamol (Berling et al, 2012; Horsmans et al, 1998).
g) Decreased serum interleukin-6 (IL-6) has been found to be associated with hepatic injury following acute acetaminophen overdose in a prospective study. It is suggested that measuring serum IL-6 or C-reactive protein (a surrogate for IL-6) levels may serve as a prognostic factor in predicting hepatic injury following an acute overdose (Waksman et al, 2001).
h) HEPATIC ENCEPHALOPATHY (HE): A model, based on a prospective and validated study was developed to predict hepatic encephalopathy in acetaminophen overdose and to identify high-risk patients for early transfer to a liver intensive care unit/transplantation facility. The most accurate model for HE included: log10 (hours from overdose to antidote treatment), log10 (plasma coagulation factors on admission), and platelet count x hours from overdose (chi-square=41.2, p less than 0.00001). HE was not seen in patients treated within 18 hours after overdose.
i) STABLE CHRONIC LIVER DISEASE: There is no evidence that stable chronic liver disease enhances the likelihood of hepatotoxicity from therapeutic use of acetaminophen.
j) ETHANOL (ACUTE or CHRONIC): In a case series of 645 patients with single-dose acetaminophen poisoning, time to initiation of NAC therapy was the most important predictor of the degree of liver injury. In a multivariate analysis, chronic alcohol abuse was an independent factor for mortality and the development of hepatic encephalopathy. Acute alcohol ingestion in chronic alcohol abusers had a protective effect against hepatic encephalopathy. In patients who were not alcohol abusers and either took an acute alcohol ingestion or did not take any alcohol, only a nonsignificant trend toward a protective effect of acute alcohol ingestion was shown (Schmidt et al, 2002). Therapeutic doses of acetaminophen do not appear to cause hepatotoxicity in chronic alcoholics (Rumack, 2002).
k) TOBACCO USE: According to a retrospective study, conducted to evaluate the effects of tobacco use on morbidity and mortality from paracetamol-induced hepatic failure, tobacco use is an independent risk factor for the development of severe hepatotoxicity, acute liver failure, and death following paracetamol overdose (Schmidt & Dalhoff, 2003).
l) AGE: A retrospective study evaluating age as a risk factor for fulminant hepatic failure and death in patients with paracetamol poisoning, determined that 40 years of age or older is considered a significant independent risk factor for the development of fulminant hepatic failure and death in patients following paracetamol overdose. However, a comparison of data showed that in the patients who were 40 years of age or older, the quantity of paracetamol taken was greater (500 mg/kg vs 448 mg/kg, respectively), the time to presentation at the hospital was greater (24 hours vs 19 hours), and the time before receiving NAC therapy was greater (30 hours vs 20 hours) compared with the patients who were less than 40 years of age, all of which may have been contributing factors to the incidence and severity of hepatotoxicity (Schmidt, 2005).
m) OBESITY: A morbidly obese 31-year-old woman (202 kg; BMI 62.1) presented to the hospital approximately 40 minutes after an acute ingestion of several medications (amounts unknown), including acetaminophen, aspirin, cephalexin, cetirizine, ibuprofen, prednisone, and a vitamin supplement. Four hours after ingestion, her serum acetaminophen level was 109.2 mcg/mL, her liver enzyme levels were normal (AST 28 units/L, ALT 48 units/L) and her INR was 1.2. At this time, N-acetylcysteine (NAC) was not administered based on the Rumack nomogram. The next day, her liver enzymes increased (AST 2067 units/L, ALT 897 units/L), indicating acute liver injury, and treatment was initiated with IV NAC. Although the patient admitted to drinking 3 alcoholic beverages daily, other causes for the liver injury were ruled out. Repeat lab studies revealed severe hepatocellular injury, with peak AST and ALT levels of 22,760 units/L and 8249 units/L, respectively, as well as grade 2 encephalopathy, acidosis (lactate 6.5 mmol/L), coagulopathy (INR 6.9), renal insufficiency (serum creatinine 2.2 mg/dL), and hypoglycemia (glucose 45 mg/dL). With continued supportive therapy and administration of NAC, the patient recovered without requiring transplantation (Lavonas et al, 2015)

a) SUMMARY: Children are less likely to develop toxic acetaminophen levels or hepatotoxicity after single acute ingestions than are adults or adolescents.
b) ACUTE OVERDOSE - Of 417 pediatric acetaminophen overdoses, 55 (13%) had toxic plasma levels, resulting in hepatotoxicity (SGOT greater than 1000 International Units/L) in only 3 (5.5%). A comparison with 639 adult cases showed toxic levels in 23.2% and hepatotoxicity in 29% of those (Rumack, 1984).
c) Pediatric overdose case presentations were found to have high transaminase levels and liver synthetic failure with disproportionately low total bilirubin levels (less than 200 mcmols/liter) compared with patients with other causes of fulminant hepatic failure. These patients also presented with a non-specific prodromal illness, often with fasting and/or vomiting (Miles et al, 1999).
d) Increased glutathione turnover rate in children may result in greater detoxification of acetaminophen (Rumore & Blaiklock, 1992).
e) INCIDENCE OF TOXICITY: Adolescents are 6 times more likely to develop liver damage and 2 times more likely to develop potentially toxic levels than children less than 6 years old (Rumack, 1986; Rumore & Blaiklock, 1992).
f) RISK FACTORS: The following are potential risk factors for hepatocellular damage in pediatric acetaminophen overdose (Alander et al, 2000):
g) CO-INGESTION OF ETHANOL: Ethanol co-ingestion resulted in significantly lower peak SGOT values in a series of 417 children overdosed with acetaminophen and who had toxic acetaminophen levels (Rumack, 1984).
h) PROGNOSTIC INDICATORS

a) ACUTE INGESTION: Acute renal failure has been described in 0.4% to 4% of patients, usually associated with hepatic injury (Prescott & Critchley, 1983; Prescott et al, 1982; Mour et al, 2005; Monteagudo & Folb, 1987; Chan et al, 1995; Brotodihardjo et al, 1992; Katzir et al, 1995; Eguia & Materson, 1997; Alkhuja et al, 2001), but may be 10% or greater in selected groups of patients with severe overdose (Prescott & Critchley, 1983; McClain et al, 1988).
b) Patients developing renal failure are more likely to have fatal overdoses than those who do not (Harrison et al, 1990a; O'Grady et al, 1988; Makin et al, 1995).
c) Isolated renal impairment, including acute tubular necrosis, without severe hepatotoxicity has been reported (Kher & Makker, 1987; Campbell & Baylis, 1992; Curry et al, 1982; Jeffery & Cafferty, 1981; Davenport & Finn, 1988; Pillans & Hall, 1985; Eguia & Materson, 1997).
d) Acute renal failure with moderate hepatocellular damage has been reported following acetaminophen overdose in a chronic alcoholic (Akca et al, 1999).
e) Back pain, proteinuria, and hematuria may occur 36 to 48 hours post-ingestion and are reported to herald renal failure (Prescott et al, 1982).
f) In a retrospective series of 36 patients with acute renal failure after acetaminophen overdose, the onset of acute renal failure was generally within 2 to 5 days of overdose and serum creatinine peaked 3 to 16 days after overdose (Eguia & Materson, 1997).
g) Non-oliguric acute tubular necrosis as a cause of acute renal failure, and associated with hepatotoxicity (without liver failure), has been reported in a 19-year-old following an overdose of 42.5 grams of acetaminophen. The patient survived following NAC and supportive therapy (Alkhuja et al, 2001).
h) Nephrotoxicity without hepatotoxicity has been associated with the presence of glutathione S-transferase-u isoenzyme (Koppel et al, 1992; Koppel et al, 1995).
i) INCIDENCE (ADOLESCENTS): In a clinical trial, there was an incidence of 8.9% acetaminophen-induced nephrotoxicity following acute severe poisoning in adolescents (n=45). No obvious predictors of nephrotoxicity were apparent in this case series (Boutis & Shannon, 2001).
j) A retrospective analysis of 17 patients with renal insufficiency following acetaminophen overdose showed that severe nephrotoxicity occurred following low-dose intoxications of acetaminophen (6 patients ingested 5000 mg), indicating that there may have been other contributing factors for the development of nephrotoxicity (ie, other nephrotoxic drugs, dehydration, preexisting renal insufficiency). In less than one-third of the patients, nephrotoxicity also occurred without the development of hepatotoxicity; in the majority of patients, nephrotoxicity resolved without dialysis (vonMach et al, 2005).

a) Metabolic acidosis has been reported within 3 to 4 hours of acetaminophen overdose in the absence of hepatotoxicity or co-ingestants, in these situations:
b) Other causes of acidosis should be ruled out.

a) LACTATE: There may be a correlation between elevated plasma lactate concentrations and elevated plasma acetaminophen concentrations on admission (Gray et al, 1987).
b) Higher arterial lactate concentrations are associated with poorer outcomes in patients with acetaminophen induced acute liver failure (Schmidt & Larsen, 2006).

a) Thrombocytopenia has developed 10 to 48 hours after ingestion in several patients (Monteagudo & Folb, 1987; Thornton & Losowsky, 1990; Fischereder & Jaffe, 1994).

a) Acetaminophen, unlike phenacetin, does NOT cause methemoglobin formation (Rumack & Matthew, 1975).

a) Pancytopenia has been reported following acute acetaminophen overdose in adults and children, but is not a common overdose manifestation (Yang et al, 2001).
b) CASE REPORT: Pancytopenia was reported in a 3.5-year-old child after she received 325 mg of acetaminophen every 2 hours for 48 hours (Douidar et al, 1994).

a) Following acetaminophen overdoses, isolated small rises in prothrombin time are common, and often occur in the absence of hepatotoxicity (Steelman et al, 2004; Whyte et al, 1999). INR may be increased in acetaminophen poisonings without hepatic damage and appears to be due to inhibition of vitamin K-dependent activation of coagulation factors (Whyte et al, 2000; Whyte et al, 1999a).

a) CASE REPORT: A 19-year-old woman presented with hepatotoxicity after ingesting a total of 12 grams of acetaminophen over 2 days. She developed a reactive plasmacytosis with thrombocytosis and life-threatening agranulocytosis, followed by a leukemoid reaction (Gursoy et al, 1996).

a) Acetaminophen overdose patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency may be more susceptible to hemolysis from oxidative stress effects on erythrocytes or to reactive neutrophilia caused by liver damage (Sklar, 2002; Kent et al, 2001).
b) CASE REPORT: Hemolytic anemia was reported in an African-American boy with glucose-6-phosphate dehydrogenase (G6PD) deficiency after an acute overdose of an unknown quantity of acetaminophen; acetaminophen level 6 hours post ingestion was 680 mcg/mL. Hemolysis continued for 8 days, with hemoglobin and hematocrit reaching nadirs of 7.6 g/dL and 22.1%, respectively. The patient recovered following IV NAC therapy. The acetaminophen metabolite responsible for oxidant stress-induced hemolysis in G6PD-deficient patients is unknown (Ruha et al, 2001).
c) CASE REPORT: A 27-year-old woman presented to the hospital following an intentional ingestion of 11 g of paracetamol (196 mg/kg). A paracetamol concentration, obtained 4 hours postingestion, was 129 mg/L, and IV NAC was administered. Within 36 hours postingestion, the patient developed jaundice (total bilirubin 145 mcmol [baseline 35 mcmol]), but liver enzymes and prothrombin time were normal. A complete blood count indicated mild anemia (hemoglobin 96 g/L) and further analysis of the bilirubin determined it to be primarily unconjugated, suggesting the development of hemolysis with a presentation of significant jaundice secondary to paracetamol overdose. Further investigation of the patient revealed that she was G6PD-deficient. Four days postingestion, the patient's elevated bilirubin concentration began to decrease (42 mcmol) (Phillpotts et al, 2014).
d) CASE REPORT: A 30-year-old woman with a history of G6PD deficiency presented approximately 12 hours after an intentional acute ingestion of 10 g acetaminophen. Laboratory data revealed an acetaminophen level of 72.3 mcg/mL, a hemoglobin level of 13.6 g/dL, a mildly elevated ALT, and evidence of indirect bilirubinemia. The patient was started on an IV acetylcysteine infusion. Forty-two hours later, repeat laboratory data demonstrated AST and ALT levels of 9118 and 8796 International Units/L, an INR of 3.4, a decreased haptoglobin level of 25 mg/dL, a LDH level of 2250 International Units/L, an unconjugated bilirubin level of 6.9 mg/dL, a total bilirubin level of 10.1 mg/dL, and her urinalysis revealed bilirubinuria without hematuria, all of which is consistent with hemolytic anemia. A repeat serum acetaminophen level was negative. Although her liver function and INR improved over the next 4 days, her anemia worsened, with her hemoglobin level decreasing to a nadir of 8.6 g/dL (Rickner & Simpson, 2015).

a) Toxic epidermal necrolysis (TEN), verified through skin biopsy and requiring hospitalization, has been described in a 7-year-old girl following the administration of 3 doses of acetaminophen (10 mg/kg). Later rechallenge with acetaminophen (a single 250 mg dose) resulted in a recurrence of TEN (Halevi et al, 2000).

a) Rhabdomyolysis accompanying coma, with no hepatic dysfunction, has been rarely reported following an acute and massive acetaminophen overdose (Yang et al, 2001).

a) Hyperglycemia is not common, but may occur as an early feature, following significant acetaminophen overdosage (Yang et al, 2001).
b) Acetaminophen may interfere with the blood glucose measurement using a yellow springs instrument glucose analyzer (YSIGA) resulting in a falsely elevated blood glucose level (Farah, 1982).
c) A case series describes 5 men who developed hyperglycemia 6 to 12 hours after acetaminophen overdose (Lawrence et al, 1995).

a) Hypoglycemia may develop 2 to 4 days following severe overdoses with associated hepatic failure (Prescott et al, 1971; Davidson & Eastham, 1966; Thomson & Prescott, 1966).

a) Reactions to acetaminophen have included bronchospasm, urticaria, hypotension and angioedema (Stricker et al, 1985; Ellis et al, 1989; Diem & Grilliat, 1990).
b) CASE SERIES: Five cases of hypersensitivity reactions have been reported in adults who ingested 500 to 1000 mg of acetaminophen and developed the following symptoms within 15 minutes to 1 hour: bronchospasm (3), urticaria (4), hypotension (1), and collapse (1) (Stricker et al, 1985).

a) CASE REPORT: A 29-year-old woman took an overdose of acetaminophen 9 times in a 21-month period. On the sixth through ninth occasions, she developed a generalized erythematous rash without associated hemodynamic or respiratory effects (Huitema et al, 1998).

a) Listed as: Paracetamol (Acetaminophen)
b) Carcinogen Rating: 3

a) In one study serum acetaminophen levels drawn less than 4 hours after overdose were useful in predicting need for NAC therapy. At acetaminophen levels greater than 200 mg/L, NAC therapy was needed; at levels less than 200 mg/L, NAC was not needed (Paloucek & Gorman, 1992).
b) In another study, an acetaminophen level of less than 100 micrograms/mL drawn between 2 and 4 hours after ingestion had a negative predictive value of .98 when compared with an acetaminophen level drawn 4 hours or more after ingestion (Douglas et al, 1994). Further studies are needed before acetaminophen levels drawn before 4 hours can be used to guide therapy.

a) An initial plasma acetaminophen level should be drawn 4 or more hours post-ingestion and plotted on the nomogram. An additional level should be drawn 4 to 6 hours after the first level and plotted on the nomogram. If either level is above the possible risk treatment line on the Rumack-Matthew Nomogram, an entire course of NAC should be administered or, if initiated, completed. If both levels are below the possible risk treatment line, then NAC therapy may be withheld or, if initiated, discontinued.
b) For assistance with ingestions of Tylenol Extended Relief(R) please call the Rocky Mountain Poison Center, toll free, at 1-800-525-6115.

a) Cp4h (in mcg/mL) = (0.59) (mg/kg dose)

a) The acetaminophen nomogram determines the need for specific antidote therapy. It is used to interpret a single plasma level obtained 4 to 24 hours after a single acute ingestion. Levels obtained before 4 hours or after 24 hours cannot be interpreted, nor can levels obtained after chronic or repeated ingestion.
b) A level above the lower or "treatment" line predicts risk for delayed hepatotoxicity and the need for the full NAC treatment regimen.
c) CAUTIONS FOR USE: This nomogram is to be used in conjunction with the POISINDEX(R) Acetaminophen Management.

a) In one study of 2534 patients treated with NAC, a half-life of greater than 4 hours had a positive predictive value of 0.22 and a negative predictive value of 0.96 in predicting peak AST greater than 1000 International Units/Liter (Douglas et al, 1994). A level above the possible toxicity line had a positive predictive value of 0.15 and a negative predictive value of 0.98 in the same group of patients. Half-life determination offers no advantage over obtaining a single level.

a) An early marker for subclinical hepatic injury following acetaminophen overdose is serum alpha glutathione S-transferase (a-GST), which is both released into and cleared from the circulation more rapidly than AST (Sivilotti et al, 1999).
b) Decreased serum interleukin-6 (IL-6) or C-reactive protein (a surrogate for IL-6) levels following acute acetaminophen overdose have been found to be statistically associated with hepatic injury and may serve as prognostic factors for predicting impending hepatic injury (Waksman et al, 2001).

a) Fatal cases usually have a bilirubin level greater than 4 mg/dL and a prothrombin time greater than twice the control or a prothrombin time ratio of 2.2 or greater on the third to the fifth day (Linden & Rumack, 1984).

a) Plasma creatinine rises more rapidly than the BUN when renal failure is present. Liver failure may keep the BUN low.

a) A retrospective study, conducted to determine the incidence and prognostic implications of hyperamylasemia in acetaminophen poisoning, revealed that the incidence and severity of hyperamylasemia (serum amylase level greater than 100 units/L) appeared to increase with the severity of hepatotoxicity induced by acetaminophen poisoning, with hyperamylasemia occurring in 57 of 76 survivors (75%) from fulminant hepatic failure and in 61 of 72 non-survivors (85%) compared with hyperamylasemia occurring in 128 of 666 patients (19%) without fulminant hepatic failure. Fifty-five of 168 patients (33%) with a serum amylase level of greater than 150 units/L either died or underwent liver transplants compared with 17 of 646 patients (2.6%) with a serum amylase level of 150 units/L or less. Acute pancreatitis was a less frequent occurrence, with only 14% of paracetamol-associated hyperamylasemia cases reported (Schmidt & Dalhoff, 2004).

a) Based on the prognostic model that was developed using stepwise forward logistic regression analysis the following formula was created to predict outcome:

a) Acetaminophen does not interfere with the prothrombin time assay (Van der Steeg et al, 1995).

a) Laboratory interferences have been reported to occur with acetaminophen on point-of-care glucose meters. Only electrode-based glucose meters are affected, with falsely increased values for glucose, increased by 79 mg/dL when acetaminophen was 332 mg/L (Osterloh, 1998)
b) In one case, a patient was admitted to the ICU with a suspected drug overdose. The handheld glucometer at the patient's bedside reported a blood glucose level of 6.1 mmol/L. A repeat measurement of the patient's glucose level, via a laboratory glucose analyzer, reported a level of 0.9 mmol/L. The patient's serum paracetamol level was 3960 mcmol/L. Further investigation of the glucose level discrepancy revealed that the laboratory analyzer uses either oxidase or hexokinase as the glucose reagent, which does not interact with paracetamol, whereas hand-held glucometers often use potassium ferricyanide/potassium ferrocyanide as glucose reagents which can interact with paracetamol, resulting in falsely elevated blood glucose readings (Ho & Liang, 2003)
c) Hyperglycemia is not common following acetaminophen overdose. An alternative method of measuring glucose should be used before insulin therapy is started.

a) An ECG should be obtained in severe acetaminophen poisonings. There have been reports of myocardial necrosis and pericarditis (Will & Tomkins, 1971; Weston et al, 1976).

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
b) ADVERSE EFFECTS/CONTRAINDICATIONS

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
b) ADVERSE EFFECTS/CONTRAINDICATIONS

a) Acetaminophen is well adsorbed by activated charcoal (Christophersen et al, 2002a; Hoegberg et al, 2002; Rose et al, 1991; Bainbridge et al, 1977; Van de Graff et al, 1982) and is most effective if given within one hour of ingestion of a liquid formulation (Anderson et al, 1999) or a tablet formulation (Christophersen et al, 2002). In normal volunteers, activated charcoal decreased the AUC of acetaminophen by 66% if administered one hour after acetaminophen ingestion (50 mg/kg) and by 22.7% when administered 2 hours after ingestion (Christophersen et al, 2002).
b) A series of 981 acetaminophen poisonings were analyzed. Patients ingesting less than 10 grams had very low risk for developing toxic serum concentrations. Patients who had ingested 10 grams or more and presented within 24 hours and were administered activated charcoal were significantly less likely to have probable or high risk serum concentrations (Buckley et al, 1999).

a) CONCLUSION: There is no reason to withhold activated charcoal in a patient with acetaminophen overdose. Activated charcoal may provide additional hepatoprotection in patients requiring NAC treatment for acetaminophen overdose.
b) ACTIVATED CHARCOAL HEPATOPROTECTION: In a prospective study of 122 patients with acetaminophen overdose requiring NAC therapy, hepatotoxicity (peak SGOT greater than 125 units/mL) developed in 4 of 82 patients receiving activated charcoal compared with 10 of 40 patients who did not receive activated charcoal. Timing of the administration of activated charcoal and NAC less than or more than 2 hours apart did not affect outcome (Spiller et al, 1994).

a) A retrospective study was conducted to determine if an AST/ALT ratio can indicate recovery from hepatotoxicity following acute acetaminophen poisoning. Analysis of cases of patients hospitalized with acetaminophen poisoning from 2001 to 2013 identified 37 patients who received NAC due to suspected severe acetaminophen poisoning and who had AST or ALT concentrations greater than 1000 International units/liter. Serial paired AST and ALT concentrations were recorded from each patient's hospital course. Each pair was classified as either post-peak or not, and AST/ALT ratios were calculated for each pair. After evaluating a total of 343 AST/ALT pairs for the 37 patients, it was determined that an AST/ALT ratio of 0.4 or less was 99% sensitive in identifying a patient whose transaminase concentrations were resolving, suggesting that for patients with no other hepatic failure indicators (eg, elevated INR, encephalopathy), the AST/ALT ratio may be a useful indicator of when to safely discontinue NAC treatment; however, further investigation is warranted (McGovern et al, 2015).

a) Obtain a plasma acetaminophen level 4 or more hours after ingestion and plot it on the Rumack-Matthew Nomogram. Levels obtained prior to 4 hours may not represent peak plasma levels and CANNOT be used to predict hepatotoxicity and need for NAC therapy. Greatest accuracy is obtained with samples done between 4 and 12 hours.

a) Ingestions of Tylenol(R) PM, which also contain diphenhydramine, have been reported to result in a delay in peak serum acetaminophen levels, most likely due to anticholinergic effects of diphenhydramine causing slowed gastric emptying (Tsang & Nadroo, 1999).
b) Concomitantly ingested drugs (particularly those with anticholinergic or opioid effects) or foods may affect gastric emptying and time to peak plasma level. Additional levels may be needed to determine the peak (Linden & Rumack, 1984; Tighe & Walter, 1994; Gesell & Stephan, 1996; Tsang & Nadroo, 1999).

a) A number of investigators have suggested that chronic ethanol exposure increases the risk of acetaminophen-induced hepatic injury. Conservative interpretation of acetaminophen levels in alcoholics has been recommended by some authors (Cheung et al, 1994; Seeff et al, 1986; Lauterburg & Velez, 1988).

a) Obtain an initial plasma acetaminophen level 4 or more hours postingestion and an additional level 4 to 6 hours after the first level and plot them on the nomogram. If either level is above the possible risk line on the Rumack-Matthew Nomogram, an entire course of NAC should be administered or, if initiated, completed. If both levels are below the possible risk line , then NAC therapy may be withheld or, if initiated, discontinued.

a) After 24 hours postingestion, the presence of acetaminophen in the plasma may be documented, but interpretation of these levels is difficult. Because of increasing evidence of the beneficial effect of NAC instituted more than 24 hours after overdose, its use is recommended in patients presenting 24 hours or more postingestion who have measurable acetaminophen levels or biochemical evidence of hepatic injury (Parker et al, 1990; Harrison et al, 1990; Keays et al, 1991; Tucker, 1998; Buckley et al, 1999a).
b) Certain serum acetaminophen assays are insensitive below 10 mcg/mL (greater than 66.16 Standard International Units (micromole/L)), rendering the Rumack-Matthew Nomogram invalid in patients who present greater than 19 hours after acetaminophen ingestion with no recordable levels. The authors recommend that these patients receive NAC therapy until 24 hours since the last acetaminophen ingestion, at which point it can be discontinued providing there is no detectable serum acetaminophen or clinical or biochemical evidence of hepatotoxicity (Donovan et al, 1999).
c) In a population-based incidence and outcome study of acetaminophen poisoning, it was determined that atypical presenters, those whose risk cannot be estimated using the Rumack-Matthew Nomogram, represented 44% of the hospitalized patients and 83% of those who suffered significant hepatic injury. This group represents patients with the poorest outcome (Bond & Hite, 1999).
d) In late presenters following acetaminophen overdose, the best prognostic marker in established hepatotoxicity is the prothrombin time. Extended courses of NAC may be given until the prothrombin time improves (Jones, 2000).

a) The most common protocol used in the US for prevention of acetaminophen-induced liver injury after acute overdose is the 72-hour oral protocol. In addition, the 21-hour IV NAC protocol is available in the US. Outside the US, the 20-hour intravenous protocol (Prescott protocol) is most commonly used. In patients who develop hepatic injury, NAC therapy should be continued until hepatic function improves.

a) Patients receiving NAC therapy should meet the following criteria:
b) EFFERVESCENT TABLET PREPARATION
c) ADVERSE EFFECTS

a) A shorter duration of oral NAC has been recommended for acute acetaminophen overdoses presenting within 24 hours of ingestion. Several small studies suggest that oral NAC loading dose of 140 mg/kg followed by 70 mg/kg every 4 hours until the serum acetaminophen level is no longer detectable and aminotransferase levels are normal, is safe and effective (Betten et al, 2007; Tsai et al, 2005; Woo et al, 2000; Woo et al, 1995). Because of the shorter hospitalization and associated costs, this protocol may be preferable in patients presenting soon after an acute ingestion.

a) This is the standard FDA-approved dosing regimen used in Europe (Prescott protocol). NAC is used for prophylaxis/prevention of acetaminophen-induced hepatic injury. LOADING DOSE: 150 mg/kg in 200 mL of 5% dextrose, infuse intravenously over 60 minutes. MAINTENANCE DOSE: 50 mg/kg in 500 mL of 5% dextrose, infuse intravenously over 4 hours followed by 100 mg/kg in 1000 mL of 5% dextrose, infuse intravenously over 16 hours (Daly et al, 2008; Prod Info ACETADOTE(R) IV injection, 2006; Prescott et al, 1979).
b) Acetadote(R) is available in 30-mL (200 mg/mL) single-dose glass vials(Prod Info ACETADOTE(R) IV injection, 2006).
c) In patients who develop hepatic injury secondary to acetaminophen, NAC therapy should be continued until serum acetaminophen concentration is undetectable and liver function improves (Smith et al, 2008).
d) To obtain more information, you can contact Cumberland Pharmaceuticals, Inc. at 1-866-767-5077.
e) CASE REPORT: A 78-year-old man, with a past medical history of coronary artery disease and renal insufficiency, intentionally ingested approximately 48 g of acetaminophen (ninety-six (96) 500-mg tablets) over a 1-hour period. Baseline laboratory data, on hospital admission, revealed a serum creatinine of 3.4 mg/dL, but normal liver enzyme levels (AST, 8 units/L; ALT, 22 units/L), bilirubin level, and prothrombin time (13.5 seconds). A serum acetaminophen level, obtained 2.25 hours postingestion, was 264 mcg/mL. Intravenous NAC was initiated 5 hours postingestion and continued for 21 hours. Because of normal liver enzyme and bilirubin levels, NAC was discontinued after 21 hours of therapy despite a serum acetaminophen concentration of 116 mcg/mL at the time NAC was discontinued. Intravenous NAC was restarted 24 hours later, at which time the patient's AST and ALT levels were 395 and 453 units/liter, respectively. Over the next few days, AST and ALT levels peaked at 4350 and 5621 units/L and his PT was 51.4 seconds. IV NAC was continued until normalization of lab values. The authors conclude that because of a possibility of delayed and erratic absorption following massive acetaminophen overdose ingestions, it is recommended that intravenous NAC should be continued until serum acetaminophen concentrations are undetectable and liver function improves (Smith et al, 2008).
f) COMPARISON OF NAC PROTOCOLS: A retrospective case review was conducted, comparing clinical outcomes of acetaminophen overdoses treated with either 20-hour IV NAC, 36-hour oral NAC, or 72-hour oral NAC. Primary outcomes that were measured included survival, liver transplant, and death. Secondary outcomes measured included development of grade III/IV hepatic encephalopathy, creatinine greater than 3.4 mg/dL, INR greater than 6.5, or a pH less than 7.3. Out of a total of 4642 cases of acetaminophen overdose reported to the Illinois Poison Center between 2002 and 2007, 795 cases were included in the study: 213 patients completed the 20-hour IV NAC protocol, 213 patients completed the 36-hour oral NAC protocol, and 369 patients completed the 72-hour oral NAC protocol. All patients had a single acute ingestion of acetaminophen, a known time of ingestion, a plasma acetaminophen concentration that was greater than 150 mcg/mL at 4 hours postingestion, and NAC treatment that was initiated within 8 hours postingestion. There were no occurrences of hepatic encephalopathy, elevated creatinine, or elevated INR within any of the 3 treatment groups. There were also no reported liver transplant cases or death in any of the 3 treatment groups. Acidosis (pH less than 3) was reported in 3 cases within the 20-hour IV treatment group and in 1 case within the 72-hour oral treatment group. However, based on the results of this study, 20-hour IV NAC protocol appeared to be as effective for acute acetaminophen poisoning when administered within 8 hours postingestion as the 36-hour and 72-hour oral NAC treatment regimens (Williamson et al, 2013).
g) PEDIATRIC
h) ADVERSE EFFECTS
i) ANAPHYLACTOID REACTIONS
j) FACIAL FLUSHING
k) PROTHROMBIN INDEX
l) DISCONTINUATION CRITERIA

a) It is recommended that NAC be given to those patients who develop acetaminophen-associated hepatic failure but cannot be risk stratified by the Rumack-Matthew Nomogram (Wolf et al, 2007).
b) In patients with hepatotoxicity or hepatic failure prolonged courses of NAC therapy may be needed. NAC should be continued, using one of the above regimens, until clinical and biochemical markers of hepatic injury improve.

a) In a series of 4 pregnant patients who delivered while receiving NAC therapy for acetaminophen overdose, it was found that the mean cord blood (in one case with fetal demise cardiac blood was used) NAC level at the time of delivery was 9.4 mcg/mL, which is within the range normally seen in patients receiving therapeutic NAC (Horowitz et al, 1997). Administering NAC to the mother as soon as possible after the overdose is the most effective means of preventing hepatotoxicity in mother and fetus (Riggs et al, 1989).
b) NAC therapy should be continued in the infant if delivered before the mother completes the entire course of therapy. Infants born with biochemical evidence of acetaminophen-induced hepatic injury should continue to receive NAC until clinical and biochemical parameters improve.

a) Sixty cases of acetaminophen overdose without evidence of teratogenesis have been reported. Twenty-four had serum levels above the nomogram line. Nine women had spontaneous abortions or stillbirths. One fetal death was recorded in the second and third trimesters. One third-trimester hepatotoxic patient delivered a 32 week stillborn during the course of NAC treatment. The plasma acetaminophen concentration in the stillborn was 360 mcg/mL (therapeutic range is 10 to 20 mcg/mL) and the autopsy showed massive hepatic necrosis (Riggs et al, 1989).

a) CONCLUSION: Although one study demonstrates an increased survival rate (16 of 23 patients) following early hemoperfusion, more controlled clinical studies need to be performed before this procedure can be considered a routine treatment for acetaminophen-induced hepatic failure (Gimson et al, 1982).

a) A molecular adsorbent recirculating system (MARS), which is a modified dialysis method using an albumin-containing dialysate that is recirculated and perfused online through charcoal and anion-exchange columns, has been used following a massive acetaminophen overdose in a patient with hepatic encephalopathy (grade II), severe acidosis, INR of 7, and hepatorenal syndrome. The patient was rejected for liver transplantation. Albumin dialysis allowed time for hepatic regeneration during conventional supportive care in this case. A course of 5 consecutive 8-hour treatments was performed (McIntyre et al, 2002; Mitzner et al, 2000).
b) CASE REPORT: Single-pass albumin dialysis (SPAD) was successfully performed on a 41-year-old woman who developed hepatic failure following an acute acetaminophen overdose. Following ICU admission (hospital day 2), the patient had fulfilled King's criteria for transplantation (pH, 7.24; INR, 7.2; model for end-stage liver disease (MELD) score of 40); however, she was deemed unsuitable for transplantation due to psychosocial comorbidities. Approximately 10 hours post-ICU admission, the patient was started on continuous veno-venous hemodiafiltration for management of lactic acidosis and oliguria. On hospital day 3, SPAD was started, consisting of 14 hours/day for 4 days and 1 day of 21 hours for a total of 77 hours. Prior to SPAD, ALT and AST levels peaked at 6828 and 15,721 units/L, respectively. Following the last day of treatment, ALT and AST levels decreased to 596 and 126 units/L, respectively, and her INR was 2.1. The patient gradually recovered and was discharged 46 days post-presentation without sequelae (Karvellas et al, 2008).

a) Acetaminophen-induced hepatitis or hepatic failure has been treated at 16 to 68 hours after an overdose for 4 to 6 hours with the Liver Dialysis System (a single-access hemodiabsorption system for treatment of serious drug overdose and for treatment of hepatic encephalopathy). During this treatment in 10 patients, acetaminophen levels dropped an average of 73%. If acetaminophen levels were still measurable in plasma, treatment was repeated 24 or 48 hours later. In this group, liver enzymes normalized 24 hours after the last treatment and no patient required a liver transplant. No adverse effects due to this treatment were noted (Ash et al, 2002).

a) CASE REPORT: A 26-year-old woman, who underwent liver transplantation, developed primary nonfunctioning of the graft on postoperative day 4, with minimal bile output, discolored bile, coagulopathy, renal failure, and a grade IV coma requiring mechanical ventilation. Due to her deteriorating clinical condition, the patient was treated with modular extracorporeal liver support (MELS), consisting of a bioreactor that is charged with human liver cells and integrated into an extracorporeal circuit with continuous single pass albumin dialysis and continuous veno-venous hemodiafiltration. The human liver cells were obtained from a discarded cadaveric graft. After a total application time of 79 hours, the patient's plasma levels of total bilirubin and ammonia significantly decreased (21.1 mg/dL and 100 mcmol/L at start of therapy, respectively, to 10.1 mg/dL and 22.7 mcmol/L at end of therapy, respectively). Her kidney function also improved with a urine output of 1325 mL/24 hours at the end of therapy compared with 45 mL/24 hours prior to therapy, and her neurological status improved from a coma grade IV to a coma grade I allowing for extubation. On postoperative day 8, a suitable graft was found, MELS was stopped, and liver transplantation was performed. The patient's recovery was uneventful (Sauer et al, 2003). While there are currently no reports of the use of this system with acetaminophen-induced fulminant hepatic failure, it might be useful as a bridge to liver transplantation.

a) Liver transplantation has a definite but limited role in the management of patients with hepatic failure from acetaminophen toxicity (Larsen et al, 1995; Makin et al, 1995).
b) Of 14 patients with poor prognosis for survival after acetaminophen overdose who were registered for transplantation, 4 of 6 (67%) survived following transplant vs 1 of 8 (12.5%) who were not transplanted. Three of 15 (20%) control patients with similar prognosis who were not registered for transplantation survived (O'Grady et al, 1991).
c) In another study of 17 patients with poor prognosis referred for liver transplant, 7 of 10 patients who received a liver transplant survived compared with 1 of 7 who did not receive a transplant (Mutimer et al, 1994).
d) Reliable prognostic indicators for fatal outcome are needed, since those patients who recover without transplantation have complete recoveries(Harrison et al, 1990) (Tournaul et al, 1992).
e) Acidosis (pH less than 7.3), a continuing rise in prothrombin time or INR on day 4, a peak prothrombin time of 180 seconds or more, and the combination of serum creatinine greater than 300 micromoles/Liter, PT greater than 100 seconds and grade III-IV encephalopathy have all shown strong correlations with fatal outcomes in patients with fulminant hepatic failure. Assuming a standard control PT of 15 seconds, then a peak International Normalized Ratio (INR) of approximately 12 or an INR greater than approximately 6.6 presumably have the same prognostic significance (Harrison et al, 1990a; O'Grady et al, 1988; O'Grady et al, 1989; Janes & Routledge, 1992; Vale, 1992; Mutimer et al, 1994).
f) The use of arterial lactate concentration may allow for earlier identification of patients at high risk of fatal acetaminophen induced liver failure and likely to benefit from listing early for liver transplantation.
g) Another study has seriously questioned the King's College lactate criteria for liver transplant. In a series of 40 patients who presented with acetaminophen-induced fulminant hepatic failure (FHF), 2 patients received transplants. Nine patients died overall: 1 who had received a transplant, 6 who arrived moribund or developed severe cerebral edema soon after presentation and transplantation was never feasible, and 2 died without transplantation. Non-transplant survival in patients who met one or both of the King's College lactate criteria (early lactate greater than 3.5 or post resuscitation lactate greater than 3) was 68% in these patients. In a series of 56 FHF patients from a related center, non-transplant survival in patients who met one or both of the King's College lactate criteria was 62%. The authors suggest that improvements in the management of FHF (particularly the prevention of cerebral edema) may make liver transplantation in acetaminophen-induced FHF necessary less often than previously believed (Gow et al, 2007).
h) A meta-analysis was conducted that compared the different prognostic criteria that were used to determine the need for liver transplantation in patients with fulminant hepatic failure secondary to acetaminophen poisoning. The criteria that was analyzed included King's criteria (pH less than 7.3 or a combination of prothrombin time (PT) of greater than 100 sec plus creatinine of greater than 300 mcmol/L plus encephalopathy grade 3 or greater), pH less than 7.3 only, PT greater than 100 sec only, PT greater than 100 sec plus creatinine greater than 300 mcmol/L plus encephalopathy grade 3 or greater, an increase in PT day 4, factor V of less than 10%, APACHE II score of greater than 15, and Gc-globulin less than 100 mg/L. Overall, in the meta-analysis, King's criteria had moderate sensitivity at 69% (range 55% to 100%), as compared with the other criteria analyzed, but it had high specificity at 92% (range 43% to 100%). Further analysis, utilizing Q values (a Q value of 1 reflects a perfect test and a Q value of 0.5 reflects an uninformative test) showed that the ability of the King's criteria to distinguish between patients requiring transplantation and those who do not seems limited, with a Q value of 0.61. However, using likelihood ratios, as an alternative method for evaluating the accuracies of diagnostic criteria (the greater the positive likelihood ratio and the lower the negative likelihood ratio, the better the criteria), the King's criteria had a positive:negative likelihood ratio of 12.33:0.29, indicating that it is a fairly accurate prognostic indicator. In comparison, the APACHE score greater than 15 criteria had a sensitivity of 81% and a specificity of 92% on the first day of patient's admission. The APACHE criteria also had the highest positive and lowest negative likelihood ratios of any criteria analyzed in the meta-analysis (16.4:0.19); however, the APACHE criteria was evaluated in only one study. Because there was only one study available, the authors concluded that further studies are needed to evaluate the efficacy of APACHE II score criteria, and in the interim, King's criteria should be used as the standard criteria, despite its moderate sensitivity (Bailey et al, 2003).
i) One study found a factor V concentration of less than 10% in patients with grade 3/4 encephalopathy and a factor VIII/factor V ratio greater than 30 to correlate with fatal outcome (Pereira et al, 1992). Another study found that, in a group of patients who did not all have grade 2 or 4 encephalopathy, these markers were not useful if measured less than 72 hours after overdose (Bradberry, 1994) (Bradberry et al, 1995).
j) In a retrospective study of 21 patients who underwent liver transplant for acetaminophen-induced liver failure 16 survived to 2 months and 5 did not. In survivors the time from ingestion to transplant was shorter (4 days vs. 6 days in non-survivors) and the pH at the time of transplant was higher (7.38 vs. 7.21 in non-survivors). A pH below 7.3 at transplantation had a sensitivity of 80% and a specificity of 94% for 2-month mortality (Devlin et al, 1995).
k) A model was developed, based on a prospective and validated study, to predict hepatic encephalopathy in acetaminophen overdose and to identify high-risk patients for early transfer to a liver intensive care unit/transplantation facility. The most accurate model for encephalopathy included: log10 (hours from overdose to antidote treatment), log10 (plasma coagulation factors on admission), and platelet count x hours from overdose (chi-square=41.2; p less than 0.00001). Hepatic encephalopathy was not seen in patients treated within 18 hours after overdose (Schiodt et al, 1999).
l) A variety of biochemical markers (ie, hemoglobin, pyruvate, calcium, and phenylalanine levels) were identified which were combined to form a prognostic model that, when applied to patients at hospital admission, appeared to accurately predict the outcome of patients with fulminant hepatic failure. The prognostic tool was derived used a cohort of 97 patients and prospectively validated with a second cohort of 86 patients admitted to the Scottish Liver Transplant Unit for acetaminophen-induced fulminant hepatic failure. Hemoglobin, pyruvate, and phenylalanine levels were significantly lower in patients who either subsequently died or underwent transplantation compared with patients who spontaneously survived. This prognostic model of outcome in acetaminophen-induced fulminant hepatic failure appears to be as accurate a predictor as utilizing King's College Hospital criteria, but at an earlier stage of the patient's condition (Dabos et al, 2005).
m) PEDIATRIC PATIENTS: Based on a retrospective review of paracetamol-induced hepatotoxicity in pediatric patients, the following indicators were associated with a poor prognosis and a need for liver transplantation (Mahadevan et al, 2006):

a) WEIGHT OF 50 KG OR MORE: The recommended dose is 1000 mg every 6 hours or 650 mg every 4 hours; may be administered as a single or repeated dose; minimum dosing interval is 4 hours; maximum single dose is 1000 mg; maximum daily dose is 4000 mg/24 hours (Prod Info OFIRMEV(R) intravenous injection, 2013).
b) WEIGHT OF LESS THAN 50 KG: The recommended dose is 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours; may be administered as a single or repeated dose; minimum dosing interval is 4 hours; maximum single dose is 15 mg/kg or 750 mg; maximum daily dose is 75 mg/kg/day or 3750 mg/24 hours (Prod Info OFIRMEV(R) intravenous injection, 2013).

a) For analgesia and antipyresis, the recommended oral dose is 650 to 1000 milligrams every 4 to 6 hours as needed, up to a maximum of 4 grams/day (Prod Info TYLENOL(R) REGULAR STRENGTH oral tablets, 2007; Prod Info TYLENOL(R) EXTRA STRENGTH chewable oral tablets, oral tablets, rapid-release oral gelcaps, oral geltabs, oral caplets, oral cool caplets, oral liquid, 2007).

a) For analgesia and antipyresis, the recommended dose is 650 milligrams administered as a rectal suppository every 4 to 6 hours is recommended, not to exceed 4 grams in 24 hours (Prod Info ACEPHEN(TM) rectal suppositories, 2006).

a) 2 to 12 years: The recommended dose is 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours; may be administered as a single or repeated dose; minimum dosing interval is 4 hours; maximum single dose is 15 mg/kg or 750 mg; maximum daily dose is 75 mg/kg/day or 3750 mg/24 hours (Prod Info OFIRMEV(R) intravenous injection, 2013).
b) 13 years or older and weighing less than 50 kg: The recommended dose is 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours; may be administered as a single or repeated dose; minimum dosing interval is 4 hours; maximum single dose is 15 mg/kg or 750 mg; maximum daily dose is 75 mg/kg/day or 3750 mg/24 hours (Prod Info OFIRMEV(R) intravenous injection, 2013).
c) 13 years or older and weighing 50 kg or more: The recommended dose is 1000 mg every 6 hours or 650 mg every 4 hours; may be administered as a single or repeated dose; minimum dosing interval is 4 hours; maximum single dose is 1000 mg; maximum daily dose is 4000 mg/24 hours (Prod Info OFIRMEV(R) intravenous injection, 2013).

a) Infants and children (less than 60 kg): The recommended dose is 10 to 15 mg/kg orally every 4 to 6 hours as needed, up to a maximum dose of 75 mg/kg/day for infants and lesser of 100 mg/kg/day or 4 g/day in children (Kraemer & Rose, 2009; Kramer et al, 2008; Kleiber, 2008; Autret-Leca et al, 2007; Playfor et al, 2006; Bauman & McManus, 2005; Goldman et al, 2004; Perrott et al, 2004; Berde & Sethna, 2002; Litalien & Jacqz-Aigrain, 2001; Cranswick & Coghlan, 2000).
b) 2 to 3 years: The recommended dose is 160 milligrams (mg) orally every 4 hours as needed, up to a maximum dose of 800 mg/24 hours (Prod Info acetaminophen oral suspension, 2006).
c) 4 to 5 years: The recommended dose is 240 milligrams orally every 4 hours as needed, up to a maximum dose of 1.2 grams/24 hours (Prod Info CHILDREN'S TYLENOL(R) oral flavor-creator liquid, oral dye-free liquid, meltaway oral tablets, oral suspension, 2007).
d) 6 to 8 years: The recommended dose is 320 milligrams orally every 4 hours as needed, up to a maximum dose of 1.6 grams/24 hours (Prod Info CHILDREN'S TYLENOL(R) oral flavor-creator liquid, oral dye-free liquid, meltaway oral tablets, oral suspension, 2007).
e) 9 to 10 years: The recommended dose is 400 milligrams orally every 4 hours as needed, up to a maximum dose of 2 grams/24 hours (Prod Info CHILDREN'S TYLENOL(R) oral flavor-creator liquid, oral dye-free liquid, meltaway oral tablets, oral suspension, 2007).
f) 11 years: The recommended dose is 480 milligrams orally every 4 hours as needed, up to a maximum dose of 2.4 grams/24 hours (Prod Info CHILDREN'S TYLENOL(R) oral flavor-creator liquid, oral dye-free liquid, meltaway oral tablets, oral suspension, 2007).
g) 12 years and older (60 kg or greater): The recommended dose is 650 to 1000 milligrams orally every 4 to 6 hours as needed, up to a maximum dose of 4 grams/24 hours (Prod Info TYLENOL(R) REGULAR STRENGTH oral tablets, 2007; Prod Info TYLENOL(R) EXTRA STRENGTH chewable oral tablets, oral tablets, rapid-release oral gelcaps, oral geltabs, oral caplets, oral cool caplets, oral liquid, 2007; Playfor et al, 2006; Greco & Berde, 2005; Berde & Sethna, 2002).

a) Infants and children (less than 60 kg): The recommended dose is 10 to 20 mg/kg rectally every 4 to 6 hours as needed, up to a maximum dose of 75 mg/kg/day for infants and lesser of 100 mg/kg/day or 4 g/day in children. A loading dose of 25 to 45 mg/kg (maximum 1000 mg) may also be given prior to maintenance dosing (Kraemer & Rose, 2009; Kleiber, 2008; Bauman & McManus, 2005; Litalien & Jacqz-Aigrain, 2001; Cranswick & Coghlan, 2000)
b) TERM INFANTS: The recommended starting dose is 30 milligrams/kilogram (mg/kg) followed by 20 mg/kg every 6 to 8 hours, not to exceed a maximum daily dose of 90 mg/kg in term infants (Van Lingen et al, 1999).
c) 3 to 6 years: The recommended dose is 120 milligrams (mg), administered as a rectal suppository, every 4 to 6 hours as needed, up to a maximum dose of 720 mg/24 hours (Prod Info ACEPHEN(TM) rectal suppositories, 2006).
d) 6 to 12 years: The recommended dose is 325 milligrams, administered as a rectal suppository, every 4 to 6 hours as needed, up to a maximum dose of 2 grams/24 hours (Prod Info ACEPHEN(TM) rectal suppositories, 2006).
e) 12 years and older (greater than 60 kg): The recommended dose is 650 milligrams, administered as a rectal suppository, every 4 to 6 hours as needed, up to a maximum dose of 4 grams/24 hours (Prod Info ACEPHEN(TM) rectal suppositories, 2006; Playfor et al, 2006).

1) The age-weight relationship is the result of the average of the 50th percentile weight for boys and girls at the given age (Behrman & Vaughn, 1983).
2) Example of dosage units are: 120-mg tablet, 120-mg wafer, 120-mg suppository, 120-mg/5 mL elixir, 120-mg/2.5 mL solution

1) An 18-month-old, 11-kg child was estimated to have ingested 45 mL of a solution of acetaminophen containing 120 mg/2.5 mL by history. Is this child above or below the 200 mg/kg threshold?
2) Find 11 kg under weight column, read across to 120-mg dosage form = 18 dosage units. Eighteen dosage units x 2.5 mL/dosage unit = 45 mL

a) In patients treated with oral NAC more than 8 hours post-ingestion, plasma acetaminophen levels were predictive of hepatotoxicity in a study of 2540 acute acetaminophen overdoses.
b) Of patients with a level corresponding to a 4-hour level of 200 to 400 mcg/mL on the nomogram, 26.7% developed a peak SGOT of greater than 1000 units/L when treatment was delayed more than 16 hours (Smilkstein et al, 1988).
c) A blood acetaminophen concentration of 15 micromoles/liter (2.26 mcg/mL) 13 hours post-ingestion was associated with the development of liver and renal toxicity in a woman being treated with isoniazid (Murphy et al, 1990).
d) TERM INFANT: A 2.88-kg term infant had an acetaminophen serum level of 133 mg/L at 6 hours after delivery. The mother had ingested 20 g of acetaminophen 3 hours prior to delivery. The infant's INR decreased from 3 to 0.94 and serum acetaminophen decreased to less than 0.1 mg/L over 48 hours following therapy with NAC infusion (Aw et al, 1999).
e) POSTMORTEM CONCENTRATIONS: The postmortem tissue and body fluid concentrations in 2 patients, a 39-year-old man (case #1) and an 18-year-old woman (case #2), who were found dead at home following intentional ingestions of unknown amounts acetaminophen and who did not have evidence of centrilobular hepatic necrosis on autopsy, are as follows (Singer et al, 2007):

a) 338 mg/kg ((RTECS, 2000))

a) 310 mg/kg ((RTECS, 2000))

a) 1944 mg/kg ((RTECS, 2000))

a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.

a) EMESIS AND LAVAGE -
b) ACTIVATED CHARCOAL -
c) CATHARTIC -

a) EMESIS AND LAVAGE -
b) ACTIVATED CHARCOAL -
c) CATHARTIC -

a) Maintain vital functions: Secure airway, supply oxygen if cyanotic, and begin supportive fluid therapy.
b) Decontaminate as specified above.
c) N-ACETYLCYSTEINE - For severely poisoned animals, load with 140 to 280 milligrams/kilogram per os or intravenously. Dilute in D5W to 5% solution and give either via stomach tube or intravenously slowly over a period of 15 to 20 minutes.
d) SODIUM SULFATE - Sodium sulfate has been used as an alternative to NAC. Dose: 50 milligrams/kilogram of a 1.6% solution in water given intravenously every 4 hours for a total of 3 to 6 treatments.
e) METHYLENE BLUE - Prepare a solution of 10 percent methylene blue in sterile saline (100 milligrams methylene blue per milliliter saline). Administer the solution intravenously to provide a dose of 1.5 milligrams/kilogram methylene blue (Rumbeiha & Oehme, 1992).
f) ASCORBIC ACID - Ascorbic acid converts methemoglobin to oxyhemoglobin. Dose at 30 milligrams/kilogram subcutaneously every 6 hours for 7 treatments. This is an adjunct therapy.
g) CORTICOSTEROIDS and ANTIHISTAMINES ARE CONTRAINDICATED. Limit physical activity to reduce anoxia hazard. Drinking water should always be available, and food may be offered 24 hours after beginning treatment.

a) Maintain vital functions: Secure airway, supply oxygen if cyanotic, and begin supportive fluid therapy.
b) Decontaminate as specified above.
c) N-ACETYLCYSTEINE - For severely poisoned animals, load with 280 milligrams/kilogram per os or intravenously. (Use cat dosages for dogs weighing 10 kilograms and less).
d) ASCORBIC ACID - Ascorbic acid converts methemoglobin to oxyhemoglobin. If methemoglobinemia is present, dose at 30 milligrams/kilogram subcutaneously every 6 hours for 7 treatments.
e) CORTICOSTEROIDS and ANTIHISTAMINES ARE CONTRAINDICATED. Limit physical activity to reduce anoxia hazard. Drinking water should always be available, and food may be offered 24 hours after beginning treatment.

a) If acetaminophen is used, the dosage must be under 100 milligrams per kilogram. For a 27 kilogram (60 pounds) dog, one 325 milligram tablet given twice daily is acceptable. If this dose does not alleviate symptoms, a veterinarian should be consulted. Another reference cites a normal oral dose for a dog as 15 milligrams/kilogram, given 3 times daily (Wallace et al, 2002).

a) No deaths occur within the first 36 hours (Francavilla et al, 1989).

1) Begin treatment immediately.
2) Keep animal warm and do not handle unnecessarily.
3) Sample vomitus, blood, urine, and feces for analysis.
4) ANIMAL POISON CONTROL CENTERS
5) Due to lack of reports of large animal intoxication with this substance, the following sections address small animals (dogs and cats) only. In the case of a poisoning involving large animals, consult a veterinary poison control center.

1) CAT
2) DOG

1) In one case of late presentation (48 hours) following an overdose of 1 gram/kilogram in an 8-month old Shetland sheepdog, S-adenosyl-L-methionine (SAMe) was administered following laboratory tests which revealed severe Heinz-body hemolytic anemia, bleeding tendencies, and a RBC glutathione concentration which was 10% of reference values. A loading dose of SAMe of 40 milligrams/kilogram was administered orally, followed by a maintenance dose of 20 milligrams/kilogram orally 6 times daily for 9 days. Other supportive measures were concurrently administered. The dog recovered (Wallace et al, 2002).

1) Ongoing treatment is symptomatic and supportive.